Dupilumab as Add-on Therapy for Management of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is characterized by pruritus, urticaria and associated with substantial patient burden. Emerging clinical trial data suggest dupilumab, an anti-IL-4Rα biologic indicated for several Type-2 inflammatory diseases, may have clinical utility for CSU. Here we present real world clinical data evaluating dupilumab as add-on therapy for CSU. We queried our tertiary academic center electronic health record for all patients with an ICD-9/10 code for urticaria with a history of dupilumab use (1/1/2010-6/30/2022). Retrospective chart review was performed to confirm CSU diagnosis, dupilumab use, patient demographics, medical history, treatments, and outcomes. Data were evaluated using summary and descriptive statistics, paired t-test, and Fisher's exact test. A total of 199 patients were identified: 39 had active CSU at time dupilumab initiation; six were excluded due to limited follow up. The most common indication for dupilumab prescription was atopic dermatitis (57.6%), followed by asthma (27.3%). Mean length of dupilumab therapy was 23 months. Following dupilumab, there was a significant reduction in number of patients on daily H1 antagonists (pre: 27 [81.8%]; post: 20 (60.1%); p=0.03), as well as total daily number of antihistamines (pre: 1.95±2.0; post: 0.13±0.2; p=0.01). For patients with moderate/severe vs. mild disease, there was greater improvement in disease control as assessed by physicians global impression of change (77% vs. 30%, p=0.02). In this real-world study, when used as add-on therapy for patients with CSU, dupilumab was associated with improved disease control and decreased H1 blocker use, suggesting a future for dupilumab as an approvedbiologic therapy for the treatment of CSU.

Hypogammaglobulinaemia and B cell lymphopaenia in Barth syndrome.

Barth syndrome (BTHS) is an X linked recessive disorder caused by a mutation in the tafazzin (TAZ) gene classically associated with the triad of neutropaenia and cardiac and skeletal myopathies. Here we present a case of BTHS in a 2-month-old male patient found to have a novel variant of the TAZ gene (hemizygous c.639G>A) leading to early termination of the tafazzin protein (p.Trp213Ter) with presumed loss of function. Our patient was found to have dilated cardiomyopathy, cyclic neutropaenia and growth delays, which in combination with genetic work-up confirmed the diagnosis of BTHS. He also experienced repeated bacterial and viral infections, prompting an immunological work-up which revealed persistent B cell lymphopaenia and hypogammaglobulinaemia. He ultimately required subcutaneous immunoglobulin replacement and GM-CSF for ongoing hypogammaglobulinaemia and neutropaenia. To our knowledge, this case is the first report of BTHS associated with B cell lymphopaenia and hypogammaglobulinaemia.

Impact of type 2 targeting biologics on acute exacerbations of chronic rhinosinusitis.

Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are associated with significant morbidity and decreased quality of life. There are sparse data assessing the real-world impact of biologics on AECRS. Objectives: We sought to determine the impact of type 2-targeting biologics on the frequency of medication use for AECRS episodes. Methods: Antibiotic and/or systemic corticosteroid courses for AECRS were identified in a retrospective study from November 2015 to February 2020, at a single academic health system. The estimated yearly rates for antibiotic and corticosteroid courses were evaluated before and after initiation of type 2 biologics. Results: One-hundred and sixty-five patients with chronic rhinosinusitis (CRS) had received either omalizumab (n = 12), mepolizumab (n = 42), benralizumab (n = 44), dupilumab (n = 61), or reslizumab (n = 6). Seventy percent had CRS with nasal polyps, and 30% had CRS without nasal polyps. All the patients had asthma. When all the biologics were combined, the estimated yearly rate for antibiotics for AECRS decreased from 1.34 (95% confidence interval [CI], 1.12-1.59) to 0.68 (95% CI, 0.52-0.88) with biologic use (49% reduction, p < 0.001). Those with frequent AECRS (three or more courses of antibiotics in the 1 year before biologic use) had a larger degree of reduction, with an estimated yearly rate of 4.15 (95% CI, 3.79-4.55) to 1.58 (95% CI, 1.06-2.35) with biologic use (n = 27; 62% reduction; p < 0.001). Within the total cohort, the estimated yearly rate for systemic corticosteroids for AECRS decreased from 1.69 (95% CI, 1.42-2.02) to 0.68 (95% CI, 0.53-0.88) with biologic use (60% reduction; p < 0.001). Conclusion: Type 2-targeting biologics reduced medication use for AECRS. This suggested that biologics may be a therapeutic option for patients with frequent AECRS.

Prevalence and characterization of asthma in hospitalized and nonhospitalized patients with COVID-19.

BACKGROUND: The Centers for Disease Control and Prevention advises that patients with moderate to severe asthma belong to a high-risk group that is susceptible to severe coronavirus disease 2019 (COVID-19). However, the association between asthma and COVID-19 has not been well-established. OBJECTIVE: The primary objective was to determine the prevalence of asthma among patients with COVID-19 in a major US health system. We assessed the clinical characteristics and comorbidities in asthmatic and nonasthmatic patients with COVID-19. We also determined the risk of hospitalization associated with asthma and/or inhaled corticosteroid use. METHODS: Medical records of patients with COVID-19 were searched by a computer algorithm (March 1 to April 15, 2020), and chart review was used to validate the diagnosis of asthma and medications prescribed for asthma. All patients had PCR-confirmed COVID-19. Demographic and clinical features were characterized. Regression models were used to assess the associations between asthma and corticosteroid use and the risk of COVID-19-related hospitalization. RESULTS: Of 1526 patients identified with COVID-19, 220 (14%) were classified as having asthma. Asthma was not associated with an increased risk of hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not increase the risk of hospitalization in a similar adjusted model (relative risk, 1.39; 95% CI, 0.90-2.15). CONCLUSIONS: Despite a substantial prevalence of asthma in our COVID-19 cohort, asthma was not associated with an increased risk of hospitalization. Similarly, the use of inhaled corticosteroids with or without systemic corticosteroids was not associated with COVID-19-related hospitalization.

Isolated Great Saphenous Vein Thrombus Is Associated with High Rates of Complications regardless of Management.

BACKGROUND: Isolated great saphenous vein thrombus (GSVT) is generally regarded as benign, and treatment is heterogeneous. Complications include thrombus propagation, new saphenous vein thrombosis, deep vein thrombosis (DVT), pulmonary embolism (PE), and symptom persistence. Our objective was to review our institution's experience with isolated GSVT to understand its natural history, the frequency of complications, real-world treatment, and the impact of proximity to the saphenofemoral junction (SFJ), on the rate of complications. METHODS: Records of patients who had lower extremity venous duplex (LEVD) demonstrating GSVT without concomitant DVT between July 2008 and June 2014 were reviewed. Demographic, medical, management, outcomes, and follow-up LEVD data were collected. RESULTS: Of 605 patients with acute GSVT, 67 limbs in 61 patients with isolated GSVT were the study group; 14.8% of patients had a hypercoagulable state, 31.1% had prior GSVT or DVT, and 23.0% of patients had malignancy; 28.4% of GSVT were observed, 13.4% were treated with aspirin/NSAIDs, and 58.2% were anticoagulated; 38.8% of limbs remained symptomatic following treatment at a mean follow-up period of 761 days; 37 limbs had GSVT <5 cm of the SFJ (group 1), and 30 had GSVT >5 cm from the SFJ (group 2). Seven patients developed PE, all in group 1 (P = 0.02). Twenty-nine limbs (43.3%) had follow-up LEVD at a mean of 23 days. In this subset, 13 patients at the initial scan (44.8%) had thrombus <5 cm of the SFJ (group 1) and 16 (55.2%) had thrombus >5 cm from the SFJ (group 2). Five limbs (17.2%) had GSVT propagation/new superficial vein thrombosis (SVT), and 6 (20.7%) developed new DVT. There was no GSVT propagation/new SVT in group 1, whereas 5 limbs (31.2%) had GSVT propagation/new SVT in group 2 (P = 0.048). DVT occurred in 2 limbs (15.3%) in group 1 and 4 limbs (25%) in group 2. CONCLUSIONS: Isolated GSVT tends to affect patients with hypercoagulable states, prior venous thromboembolism, malignancy, or recent surgery. Management is heterogeneous, and type of treatment does not seem to affect outcomes. Patients with GSVT have significant risk of persistent symptoms, recurrence, DVT, and PE. GSVT within 5 cm of the SFJ seemed to be associated with an increased rate of PE. GSVT more than 5 cm from the SFJ seemed to be associated with propagation/new SVT. Proximity to the SFJ did not impact occurrence of DVT.

Elevated Peak Systolic Velocity and Velocity Ratio from Duplex Ultrasound are Associated with Hemodynamically Significant Lesions in Arteriovenous Access.

BACKGROUND: Duplex ultrasound (DUS) is reliably used to detect lesions in the peripheral and carotid arterial beds and venous system. Although commonly used in clinical practice, duplex criteria to define lesions in arteriovenous access are not well characterized. This study will define the optimal Doppler-derived peak systolic velocity (PSV) and velocity ratio (VR) to identify >50% lesions in arteriovenous fistulas (AVF) and arteriovenous grafts (AVG). METHODS: This retrospective analysis includes patients with both DUS and fistulogram within 30 days. DUS-derived PSV and VR were recorded for 3 segments of each access and compared with fistulograms of the same 3 segments of each AV access. Receiver operating characteristic (ROC) was used to determine the optimal DUS criteria for diagnosis of >50% stenosis. RESULTS: Fifty pairs of imaging in 40 patients were available for analysis. Mean PSV and VR for segments with greater than 50% stenosis were significantly greater than those without; mean PSV of 480 cm/sec vs. 297 cm/sec (P < 0.001) and mean VR of 3.81 vs. 2.09 (P < 0.001). The ROC analysis demonstrated an optimal PSV of 404 and VR of 2.2 to diagnose >50% stenosis with area under the curve of 0.825 and 0.821 for PSV and VR, respectively. PSV of 500 had sensitivity (Se) of 0.60, specificity (Sp) of 0.86, positive predictive value (PPV) of 0.72, and negative predictive value (NPV) of 0.78. VR of 3.0 had Se of 0.52, Sp of 0.91, PPV of 0.77, and NPV of 0.75. CONCLUSIONS: DUS-derived PSV of 400 cm/sec and VR of 2.25 have good discrimination to predict greater than 50% stenosis in AVFs and AVGs. Given the broad range of velocities in AV accesses, a threshold of PSV greater than 500 cm/sec and VR greater than 3.0, will reliably identify graft-threatening lesions. Se and Sp of PSV 500 are 0.596 and 0.854, respectively. Se and Sp for VR 3.0 are 0.519 and 0.894, respectively.

Upper Extremity Steal Syndrome Is Associated with Atherosclerotic Burden and Access Configuration.

BACKGROUND: Clinically significant steal syndrome occurs in a subset of dialysis patients with arteriovenous (AV) access. Factors associated with steal are poorly understood. Severe symptoms require access revision or sacrifice, potentially jeopardizing access options. Our objective was to review our dialysis access experience to identify factors associated with significant steal syndrome. METHODS: We reviewed all adult patients undergoing their first permanent upper extremity access, AV fistula (AVF) or AV graft (AVG), between January 2008 and July 2011 at a single center. Medical, demographic, and access characteristics were collected from our electronic medical record and a local dialysis center's database. Patients who required correction of steal syndrome were compared with the larger access cohort. Statistical analysis included Fisher's exact test and χ(2) for noncontinuous variables and unpaired t-test for continuous variables. RESULTS: Of the 303 patients, 15 required correction for steal syndrome (8 of 232 AVF and 7 of 71 AVG). Eight were ligated; 2 were initially banded, then ligated; and 5 underwent distal revascularization with interval ligation. Coronary artery disease was more prevalent in steal syndrome patients (66.7% vs. 25%, P = 0.001); the same was found with peripheral arterial disease (40% vs. 13.8%, P = 0.02). Furthermore, more patients with steal syndrome were on clopidogrel for cardiovascular reasons (40% vs. 9%, P = 0.002). Steal syndrome only developed with AVF and AVG using brachial artery inflow. No cases of steal syndrome arose from radial/ulnar inflow (P = 0.03). All AVG with steal syndrome had a straight configuration; no looped AVG developed steal (P = 0.02). Other patient characteristics such as age, sex, race, hypertension, diabetes mellitus, congestive heart failure, cerebrovascular accident, cause of end-stage renal disease, and other medication history were not different between groups. CONCLUSIONS: Clinically significant steal syndrome is associated with disease in coronary and peripheral arterial beds. In addition, the use of brachial artery inflow and straight AVG configuration is associated with steal syndrome. Consideration should be given to construction of access using smaller forearm arteries and looped AVG configuration in patients with high risk for steal. In addition, such patients may require more vigilant monitoring for development of steal after access construction.

The end stage of dialysis access: femoral graft or HeRO vascular access device.

BACKGROUND: Maintaining and establishing vascular access in end-stage renal disease (ESRD) patients is complicated when they are poor candidates for traditional upper extremity access. Our objective was to compare our experience with 2 alternative dialysis accesses, the femoral arteriovenous graft (fAVG) and the Hemodialysis Reliable Outflow (HeRO), in patients with limited remaining options. METHODS: A single institution, retrospective review of ESRD patients with fAVG or HeRO placed between May 2009 and February 2013 was performed. Adult patients were selected by reviewing all arteriovenous grafts placed at a single institution. Patient demographics, medical history, access characteristics, and outcomes were recorded from both institutional and dialysis center databases. Data were evaluated using Fisher's exact test, unpaired t-test for continuous variables, log-rank test, and univariate analysis. RESULTS: A total of 56 accesses in 43 unique patients met these criteria: 35 fAVG and 21 HeRO; with 1 HeRO patient lost immediately to follow-up. Clinical variables were similar except the HeRO group had more diabetic patients (60% HeRO, 22.9% fAVG; P = 0.01). The average number of years on hemodialysis was 7.0 ± 1.0 for fAVG and 5.7 ± 0.9 for HeRO (P = 0.41). Primary patency was 40.5%, 18.7%, and 14.9% for fAVG and 29.0%, 29.0%, and 0% for HeRO at 6 months, 12 months, and 2 years (P = 0.67), respectively. Assisted primary patency was also similar, with 43.8%, 29.4%, and 13.8% for fAVG and 34.8%, 34.8%, and 17.4% for HeRO at 6 months, 12 months, and 2 years (P = 0.81), respectively. Secondary patency was 62.6%, 50.6%, 19.3% for fAVG and 68.0%, 53.5%, 38.3% for HeRO at 6 months, 12 months, and 2 years (P = 0.69), respectively. Average number of interventions to maintain patency for fAVG was 1.1 ± 1.47 and 1.65 ± 2.52 for HeRO (P = 0.35). Infectious complications occurred in 29% of fAVG and 15% of HeRO (P = 0.33). CONCLUSIONS: Patients who received either fAVG or HeRO experience poor access patency. ESRD patients who receive either of these procedures appear to be at the end stage of available access options.

On the role of PDZ domain-encoding genes in Drosophila border cell migration.

Cells often move as collective groups during normal embryonic development and wound healing, although the mechanisms governing this type of migration are poorly understood. The Drosophila melanogaster border cells migrate as a cluster during late oogenesis and serve as a powerful in vivo genetic model for collective cell migration. To discover new genes that participate in border cell migration, 64 out of 66 genes that encode PDZ domain-containing proteins were systematically targeted by in vivo RNAi knockdown. The PDZ domain is one of the largest families of protein-protein interaction domains found in eukaryotes. Proteins that contain PDZ domains participate in a variety of biological processes, including signal transduction and establishment of epithelial apical-basal polarity. Targeting PDZ proteins effectively assesses a larger number of genes via the protein complexes and pathways through which these proteins function. par-6, a known regulator of border cell migration, was a positive hit and thus validated the approach. Knockdown of 14 PDZ domain genes disrupted migration with multiple RNAi lines. The candidate genes have diverse predicted cellular functions and are anticipated to provide new insights into the mechanisms that control border cell movement. As a test of this concept, two genes that disrupted migration were characterized in more detail: big bang and the Dlg5 homolog CG6509. We present evidence that Big bang regulates JAK/STAT signaling, whereas Dlg5/CG6509 maintains cluster cohesion. Moreover, these results demonstrate that targeting a selected class of genes by RNAi can uncover novel regulators of collective cell migration.